Protective effects of L-pGlu-(2-propyl)-L-His-L-ProNH2, a newer thyrotropin releasing hormone analog in in vitro and in vivo models of cerebral ischemia

In the present study, the newly synthesized TRH analog (l-pGlu-(2-propyl)-l-His-l-ProNH₂; NP-647) was evaluated for its effects in in vitro (oxygen glucose deprivation (OGD)-, glutamate- and H₂O₂-induced injury in PC-12 cells) and in vivo (transient global ischemia) models of cerebral ischemic injury. PC-12 cells were subjected to oxygen and glucose deprivation for 6 h. Exposure of NP-647 was given before and during OGD. In glutamate and H₂O₂ induced injury, exposure of NP-647 was given 1, 6 and 24 h prior to exposure of glutamate and H₂O₂ exposure. NP-647, per se found to be non-toxic in 1-100 μM concentrations. NP-647 showed protection against OGD at the 1 and 10 μM. The concentration-dependent protection was observed in H₂O₂- and glutamate-induced cellular injury. In in vivo studies, NP-647 treatment showed protection of hippocampal (CA1) neuronal damage in transient global ischemia in mice and subsequent improvement in memory retention was observed using passive avoidance retention test. Moreover, administration of NP-647 resulted in decrease in inflammatory cytokines TNF-α and IL-6 as well as lipid peroxidation. These results suggest potential of NP-647 in the treatment of cerebral ischemia and its neuroprotective effect may be attributed to reduction of excitotoxicity, oxidative stress and inflammation.